4-phenoxy acetamido-2 3-dimethyl-1-phenyl-5-pyrazolones

ABSTRACT

MEDICAMENT COMPRISING 4-(ARYLOXYACETAMIDS)-2,3,DIMETHYL-1-PHENYL-5-PYRAZOLONE HAVING AS GENERAL FORMULA:   1-(C6H5-),2,3-DI(CH3-),4-((2-R2,4-R1-PHENYL)-O-CH2-CO-   NH-),5-(O=)-3-PYRAZOLINE   EACH OF SIGNS R1, R2 REPRESENTING AN ALKYL OR ALKOXY GROUP HAVING FROM 1 TO 4 CARBON ATOMS OR A HALOGEN ATOM.

'. 6 United States Patent ce 3,634,449 Patented Jan. 11, 1972 3,634,449 TABLE I 4-PHENOXY ACETAMlDO-2,3-DlMETHYL-1- A O, a/ a PHENYL-S-PYRAZOLONES Jean Cahn, Paris, France. Edmond Marie Canonne, 5 i v iifi geneva, Switzerland, and Guy Lejeune, Hauts de Seine, fi l aston Arthur Francois Ligny Seine-Saint-Denis and am o-pynn Dario Claude Fulvio Modigliani, Paris, France as- R2 Tests signors to Laboratories Valda, Paris, France 3,0 01 H 371-5 177478 1220 No Drawing. Filed July 9, 1969, Ser. No. 840,495 2 89 E 2 $5328 3 2'3; Claims priority, application France, July 15, 1968, 10

1 Exceediug 12 g./kg. Int. Cl. C07d 49/02 CL 260 310 A 4 Claims Pharmacological properties By way of example, a study has been made of anti- 15 inflammatory activity, analgesic activity and antipyretic ABSTRACT OF THE DISCLGSURE Medicament comprising 4-(aryloxyacetamids)-2,3 dimethyl-l-phenyl-S-pyrazolone having as general formula:

0 onto ONH-O==OCH3 o: N-CH R2 Cal-Ir each of the signs R R representing an alkyl or alkoxy group having from 1 to 4 carbon atoms or a halogen atom.

This invention has for its object new medicaments having an antipyretic, anti-inflammatory and analgesic action comprising 4 (aryloxyacetamids)-2,3-dimethyl-1-phenyl- 5-pyrazolone complying with the following formula:

0:!) NCHa R2 I N (IJBHE This thus refers to 4-(aryloxyacetamids)-2-3-dimethyl l-phenyl-S pyrazolone. In the formula R R may be alkyl groups such as methyl, ethyl, isopropyl or n-butyl, or alkoxy groups such as methoxy, ethoxy, isopropoxy or n-butoxy, or halogens such as fluorine, chlorine, bromine or iodine.

The 4 (aryloxyacetamids) 2-3 dimethyl-l-phenyl-S- pyrazolone are prepared by commencing with acid chloride of aryloxyacetic acids that is made to react on the 4- amino-2-3 dimethyl-l-phenyl-S pyrazolone in a pyridic medium or making the acids 4-(aryloxyacetics) react on the 4 amino-l-3-dimethyl-l-phenyl-S-pyrazolone in the presence of oxychloride of phosphorus.

As has been stated, these compounds obtained according to the process described hereafter have pharmacological properties, for experiments carried out on animals in vivo and in vitro have revealed on antipyretic, anti-inflammatory and analgesic action, this action being accompanied by less toxicity than that shown by antipyrin.

We give hereafter complementary information about the toxicity of the products, their method of preparing, formulas by medical weight, clinical observations, in order to make the invention clear.

Toxicity To illustrate the pharmacological properties of some of the compounds described hereafter, the following table shows the toxicity and the new DL SO in rats, a phenacetin mixture plus amidopyrin in equal parts being taken equally as comparison substance. I

activity of the derivatives of the references 3017 and 3357 given in the previous table.

Anti-inflammatory activity.This has been measured by the oedema test with carragenine of the rats paw. Compared to that of anti-pyrin, the activity of the two bodies studied has shown that they are very similar to each other.

Analgesic activity.TWo tests were made for measuring the analgesic effect: on the one hand the hot plate test (heat stimulus), on the other hand, the cramping test (chemical stimulus). Mice were used for both tests.

The last test, a particularly severe one, undoubtedly shows that the 3357 derivative is endowed with an accentuated analgesic power, much greater than that of antipyrin.

The results are summarised as follows:

C RAMPING TEST Number of twists References physiological water. 127 Arabic gum 146 Antipyrin:

150 mg./kg 143 300 mg-lkg 118 Derivative 3017:

300 mg./kg 110 600 mg./kg 106 Derivative 3357:

300 mg./kg 15 600 lug/kg 54 METHOD OF PREPARATION There is incorporated in a flask 20.3 g. of 4-amino-2-3 dimethyl-l-phenyl-S-pyrazolone 200 ml. of anhydrous benzine. The acid is made to react contributing the radicals sought. After the three bodies are completely dissolved 10 g. of bentonite are poured, and 15.8 g. of oxychloride of phosphorus are added drop by drop. While vigorously shaking, one heats to a flow during one hour. After cooling, the mixture is watered with an equal volume of water. The aqueous phase is isolated that is made alkaline with soda 4 N. After leaving standing for the night, one checks to see that the pH is still alkaline. Filtering is then effected on a Buchner and washing with water is done until the pH is neutral.

After drying, the product is purified with alcohol at boiling temperature, the inert phase is filtered and the alcoholic fraction is allowed to remain at ambient temperature.

The crystals obtained are filtered on the Buchner and washed with 95 alcohol. A second and third crystallization are done with 50 alcohol.

EXAMPLE 1 There is incorporated in a flask: 18.65 g. of parachlorophenoxy-acetic acid, 20.3 g. of 4-amino-2-3-dimethyl-1- phenyl-S-pyrazolone, 200 ml. of anhydrous benzine. One thus obtains 4 para-chloro-(phenoXy-acetamido)-2-3-dimethyl 1 phenyl-S-pyrazolone. (M.P.=177178 C.) soluble in absolute alcohol and in 50 alcohol, insoluble in water.

EXAMPLE 2 There is incorporated in a flask: 18.2 g. of para-methoxy-phenoXy-acetic acid, 20.3 g. of 4-amino-2,3-dimethyl-1-phenyl-5-py1'azolone, 200 ml. of benzine. One obtains 4 (paramethoXy-phenoxy-acetamido) 2-3-dimethyl-1- phenyl-S-pyrazolone. M.P.=l37l38 C.

EXAMPLE 3 There is incorporated in a flask: 20.4 g. of para-chloro ortho methyl phenoxy acetic acid, 20.3 g. of 4-amino 2-3- dimethyl-l-phenyl-S-pyrazolone. The body obtained is 4- (para-chloro-orthomethyl-phenoxy-acetamido) 2 3-dimethyl-l-phenyl-S-pyrazolone. M.P.=l58-159 C.

These bodies are obtained with a field in the vicinity of a theoretical 50% The new medicament can be made up in the form of a compound, a suppository, a pill, a tablet, pomade, an injectable phial or a gelloid.

MEDICAL WEIGHT FORMULAS (1) Tablet G. Para chloro (phenoxy-acetamido)-2-3-dimethyl- I-phenyl-S-pyrazolone 0.50 Quant. suff. of excipient for a tablet.

(2) Suppository (Para-methoxy-phenoXy-acetamido) 2 3 dimethyl-l-phenyl-S-pyrazolone 0.50 Quant. suff. of excipient to make a suppository of about 2 g.

(3) Pill (Para-chloro-ortho-methyl-phenoxy-acetamido) 2- 3 dimethyl 1 phenyl 5 pyrazolone 0.25 Para-chloro (phenoxy-acetamido) 2 3 dimethyl 1 phenyl 5 pyrazolone 0.25 Quant. suff. of excipient for a pill.

(4) Cachet Para-chloro (phenoXy-acetamido) 2 3 dimethyl 1 phenyl 5 pyrazolone 0.25 (Para-chloro-ortho-phenoXy-acetamido) 2 3 dimethyl 1 phenyl 5 pyrazolone 0.25

Quant. sulf. of lactose for a cachet.

(5) Tube of pomade (6) Injectable phial (Para-methoxy-phenoXy-acettmido) 2 3 dimethyl-l-phenyl-S-pyrazolone Quant. suff. excipient for a 5 ml. injectable phial.

(7) Gelloid (4 para-chloro-ortho-methyl-phenoxy-acetarnido)- 2-3-dimethyl-l-phenyl-S-pyrazolone 0.40 Quant. sutf. excipient for one gelloid.

4 CLINICAL CASES OB SERVED Observation No. 1

Mrs. Martine D.

36 years of age Patient suffering from very painful rheumatoid polyarthritis Swelling of the joints, Sedimentation speed distinctly diminished ,Treatment: 4 gelloids of Formula No. 7 per day for 15 days Evolution: favourable Tolerance: perfect Observation No. 2

Observation No. 3

Mrs. Bernadette H.-

65 years of age Coxarthrosis of the right thigh Treatment: 4 to 5 tablets per day of Formula No. 1 as attacking treatment 2 to 3 tablets a day as maintenance treatment Evolution: very favourable Tolerance: perfect Observation No. 4

Miss Simone R.-

26 years of age Sub-feverish when fever abated during influenza Treatment: 2 cachets of Formula No. 4 per day Evolution: very favourable. Disappearance of cephalitis and return to normal temperature the third day Tolerance: perfect Observation No. 5

Miss Micheline T.

19 years of age Catamial pains occurring at each monthly period Treatment: 3 pills of formula No. 3 for the first day of the period, and 2 pills on the second and third days Evolution: very favourable Pains calmed. There was no increase of the menstrual flow Tolerance: gastrically perfect Observation No. 6

Mr. Jean C.-

9 years of age Influenza with 38.5 C. fever. Intense cephalitis and tiredness Treatment: /2 tablet of formula No. 1 four times a day during 4 days. Cured on the 3rd day Tolerance: perfect Observation N0. 7

Mr. Jacques C.

63 years of age Tendinitis, following strain during sports; intense pain Treatment: 4 applications of the balm of formula N0. 5

per day Very favourable prognostic Result: obtained in 10 days Tolerance: perfect cutaneously 5 We claim: 1. A 4 (aryloxyacetamide) 2 3 dimethyl-l-phenyl- S-pyrazolone, of the formula:

(|)CH2CONHC C-CH3 each of the signs R R representing an alkyl or alkoxy group having from 1 to 4 carbon atoms or a halogen atom.

2. A compound according to claim 1, comprising 4- para-chloro- (phenoxy acetamido) -2-3-dimethyl-1-pheny1- S-pyrazolone.

3. A compound according to claim 1, comprising 4- (para-methoxy-phenoxy-acetamido) 2 3 dimethyl-lpheny1-S-pyrazolone.

4. A compound according to claim 1, comprising 4- (para chloro ortho methyl phenoxy acetamido)- 2-3-dimethyl-l-phenyl-S-pyrazolone.

References Cited UNITED STATES PATENTS OTHER REFERENCES Chemical Abstracts vol 53: 4564 g. (1959) Miura et a1.

5. D. WINTERS, Primary Examiner HENRY R. JILES, Assistant Examiner 

